Mitochondria-dependent synthetic small-molecule vaccine adjuvants for influenza virus infection.

Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors-such as aging, pregnancy, and genetic polymorphisms-influence efficacies of vaccines adjuvanted with Toll-like receptor (TLR) or known pattern-recognition receptor (PRR) agonists. Although PRR independent adjuvants (e.g., oil-in-water emulsion and saponin) are emerging, these adjuvants induce some local and systemic reactogenicity. Hence, new TLR and PRR-independent adjuvants that provide greater potency alone or in combination without compromising safety are highly desired. Previous cell-based high-throughput screenings yielded a small molecule 81 [N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide], which enhanced lipopolysaccharide-induced NF-κB and type I interferon signaling in reporter assays. Here compound 81 activated innate immunity in primary human peripheral blood mononuclear cells and murine bone marrow-derived dendritic cells (BMDCs). The innate immune activation by 81 was independent of TLRs and other PRRs and was significantly reduced in mitochondrial antiviral-signaling protein (MAVS)-deficient BMDCs. Compound 81 activities were mediated by mitochondrial dysfunction as mitophagy inducers and a mitochondria specific antioxidant significantly inhibited cytokine induction by 81. Both compound 81 and a derivative obtained via structure-activity relationship studies, 2F52 [N-benzyl-N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] modestly increased mitochondrial reactive oxygen species and induced the aggregation of MAVS. Neither 81 nor 2F52 injected as adjuvants caused local or systemic toxicity in mice at effective concentrations for vaccination. Furthermore, vaccination with inactivated influenza virus adjuvanted with 2F52 demonstrated protective effects in a murine lethal virus challenge study. As an unconventional and safe adjuvant that does not require known PRRs, compound 2F52 could be a useful addition to vaccines.

Stochastic transitions: Paths over higher energy barriers can dominate in the early stages.

The time evolution of many physical, chemical, and biological systems can be modeled by stochastic transitions between the minima of the potential energy surface describing the system of interest. We show that in cases where there are two (or more) possible pathways that the system can take, the time available for the transition to occur is crucially important. The well-known results of the reaction rate theory for determining the rates of transitions apply in the long-time limit. However, at short times, the system can, instead, choose to pass over higher energy barriers with a much higher probability, as long as the distance to travel in phase space is shorter. We construct two simple models to illustrate this general phenomenon. We also apply a version of the geometric minimum action method algorithm of Vanden-Eijnden and Heymann [J. Chem. Phys. 128, 061103 (2008)] to determine the most likely path at both short and long times.

Structure-activity relationship studies in substituted sulfamoyl benzamidothiazoles that prolong NF-κB activation.

In the face of emerging infectious diseases, there remains an unmet need for vaccine development where adjuvants that enhance immune responses to pathogenic antigens are highly desired. Using high-throughput screens with a cell-based nuclear factor κB (NF-κB) reporter assay, we identified a sulfamoyl benzamidothiazole bearing compound 1 that demonstrated a sustained activation of NF-κB after a primary stimulus with a Toll-like receptor (TLR)-4 agonist, lipopolysaccharide (LPS). Here, we explore systematic structure-activity relationship (SAR) studies on compound 1 that indicated the sites on the scaffold that tolerated modification and yielded more potent compounds compared to 1. The selected analogs enhanced release of immunostimulatory cytokines in the human monocytic cell line THP-1 cells and murine primary dendritic cells. In murine vaccination studies, select compounds were used as co-adjuvants in combination with the Food and Drug Administration approved TLR-4 agonistic adjuvant, monophosphoryl lipid A (MPLA) that showed significant enhancement in antigen-specific antibody titers compared to MPLA alone. Additionally, our SAR studies led to identification of a photoaffinity probe which will aid the target identification and mechanism of action studies in the future.

Turing Instability in the Solid State: Void Lattices in Irradiated Metals.

Turing (or double-diffusive) instabilities describe pattern formation in reaction-diffusion systems, and were proposed in 1952 as a potential mechanism behind pattern formation in nature, such as leopard spots and zebra stripes. Because the mechanism requires the reacting species to have significantly different diffusion rates, only a few liquid phase chemical reaction systems exhibiting the phenomenon have been discovered. In solids the situation is markedly different, since species such as impurities or other defects typically have mobilities ∝exp(-E/k_{B}T), where E is the migration barrier and T is the temperature. This often leads to mobilities differing by several orders of magnitude. Here, we use a simple, minimal model to show that an important class of emergent patterns in solids, namely void superlattices in irradiated metals, could also be explained by the Turing mechanism. Analytical results are confirmed by phase field simulations. The model (Cahn-Hilliard equations for interstitial and vacancy concentrations, coupled by generation and annihilation terms) is generic, and the mechanism could also be responsible for the patterns and structure observed in many solid state systems.

Impact of improved observed hand hygiene on bloodstream infection rates in Ireland. A prospective segmented regression analysis, 2009-2016.

Participation in European surveillance for bloodstream infection (BSI) commenced in Ireland in 1999 with all laboratories (n = 39) participating by 2014. Observational hand hygiene auditing (OHHA) was implemented in 2011. The aim of this study was to evaluate the impact of OHHA on hand hygiene compliance, alcohol hand rub (AHR) procurement and the incidence of sensitive and resistant Staphylococcus aureus and Enterococcus faecium and faecalis BSI. A prospective segmented regression analysis was performed to determine the temporal association between OHHA and outcomes. Observed hand hygiene improved from 74.7% (73.7-75.6) in 2011 to 90.8% (90.1-91.3) in 2016. AHR procurement increased from 20.1 l/1000 bed days used (BDU) in 2009 to 33.2 l/1000 BDU in 2016. A pre-intervention reduction of 2% per quarter in the ratio of methicillin sensitive Staphylococcus aureus BSI/BDU stabilized in the time period after the intervention (P < 0.01). The ratio of Methicillin resistant Staphylococcus aureus (MRSA) BSI/BDU was decreasing by 5% per quarter pre-intervention, this slowed to 2% per quarter post intervention, (P < 0.01). There was no significant change in the ratio of vancomycin sensitive (P = 0.49) or vancomycin resistant (P = 0.90) Enterococcus sp. BSI/BDU post intervention. This study shows national OHHA increased observed hand hygiene compliance and AHR procurement, however there was no associated reduction in BSI.

Effectiveness of a shared team approach between nurses and doctors for improved risk factor management in survivors of stroke: a cluster randomized controlled trial.

BACKGROUND AND PURPOSE: Limited evidence exists on the benefits of organized care for improving risk factor control in patients with stroke or transient ischaemic attack. The effectiveness of an individualized management programme in reducing absolute cardiovascular disease risk in this high-risk population was determined. METHODS: This was a prospective, multicentre, cluster-randomized controlled trial with blinded assessment of outcomes and intention-to-treat analysis. Patients hospitalized for stroke/transient ischaemic attack and aged ≥18 years were recruited from four hospitals. General practices treating recruited patients were randomized to provide either usual care or an individualized management programme comprising nurse-led education and review of care plans by stroke specialists in addition to usual care. The primary outcome was a change in cardiovascular Framingham Risk Score between baseline and 12 months. RESULTS: From January 2010 to November 2013, 156 general practices (280 patients) were randomly assigned to usual care (control) and 159 (283 patients) to the intervention. The median age was 70.1 years; 65% were male. Overall, >80% of participants were prescribed recommended secondary prevention therapies at baseline. The primary efficacy analysis comprised 533 participants, with 30 either dying or lost to follow-up. In adjusted analyses, no significant between-group difference was found in the cardiovascular risk score at 12 months (0.04, 95% confidence interval -1.7, 1.8). CONCLUSIONS: The effectiveness of an organized secondary prevention programme for stroke may be limited in patients from high-performing hospitals with regular post-discharge follow-up and communication with general practices.

Effect of stocking rate and animal genotype on dry matter intake, milk production, body weight, and body condition score in spring-calving, grass-fed dairy cows.

The objective of the experiment was to quantify the effect of stocking rate (SR) and animal genotype on milk production, dry matter intake (DMI), energy balance, and production efficiency across 2 consecutive grazing seasons (2014 and 2015). A total of 753 records from 177 dairy cows were available for analysis: 68 Holstein-Friesian and 71 Jersey × Holstein-Friesian (JxHF) cows each year of the experiment under a pasture-based seasonal production system. Animals within each breed group were randomly allocated to 1 of 3 whole-farm SR treatments defined in terms of body weight per hectare (kg of body weight/ha): low (1,200 kg of body weight/ha), medium (1,400 kg of body weight/ha), and high (1,600 kg of body weight/ha), and animals remained in the same SR treatments for the duration of the experiment. Individual animal DMI was estimated 3 times per year at grass using the n-alkane technique: March (spring), June (summer), and September (autumn), corresponding to 45, 111, and 209 d in milk, respectively. The effects of SR, animal genotype, season, and their interactions were analyzed using mixed models. Milk production, body weight, and production efficiency per cow decreased significantly as SR increased due to reduced herbage availability per cow and increased grazing severity. As a percentage of body weight, JxHF cows had higher feed conversion efficiency, higher DMI and milk solids (i.e., kg of fat + kg of protein) production, and also required less energy intake to produce 1 kg of milk solids. The increased production efficiency of JxHF cows at a similar body weight per hectare in the current analysis suggests that factors other than individual cow body weight contribute to the improved efficiency within intensive grazing systems. The results highlight the superior productive efficiency of high genetic potential crossbred dairy cows within intensive pasture-based milk production systems at higher SR where feed availability is restricted.

ASPREE-D: Aspirin for the prevention of depression in the elderly.

BACKGROUND: Not only is depression associated with increased inflammation but inflammation is a risk factor for the genesis of depression. Many of the environmental risk factors for depression are transduced through inflammatory signaling. Anti-inflammatory agents show promise for the management of depression in preclinical, epidemiological, and early clinical studies. This opens the door to the potential for anti-inflammatory agents to treat and prevent depression. There are no evidence-based pharmacotherapies for depression prevention. METHOD: ASPREE-D, aspirin in the prevention of depression in the elderly, is a sub study of ASPREE, which explores the potential of aspirin to prevent a range of inflammation related disorders in the elderly. With a sample size of 19,114, and a duration of 5 years, this placebo controlled study will be one of the largest randomized controlled trials in psychiatry and will provide definitive evidence on the ability of aspirin to prevent depression. RESULTS: This paper presents the rationale for the study and presents a summary of the study design. CONCLUSIONS: ASPREE-D may not only define novel therapy but will provide mechanistic proof of concept of the role of inflammation in depression.

Epidemiology and molecular typing of VRE bloodstream isolates in an Irish tertiary care hospital.

OBJECTIVES: Ireland has the highest rate of vancomycin-resistant Enterococcus faecium (VREfm) isolated from blood of nosocomial patients in Europe, which rose from 33% (110/330) in 2007 to 45% (178/392) in 2012. No other European country had a VREfm rate from blood cultures of >25%. Our aim was to elucidate the reasons for this significantly higher rate in Ireland. METHODS: The epidemiology and molecular typing of VRE from bloodstream infections (BSIs) was examined in a tertiary care referral hospital and isolates were compared with those from other tertiary care referral centres in the region. RESULTS: The most common source of VRE BSIs was intra-abdominal sepsis, followed by line-related infection and febrile neutropenia. Most of the isolates were positive for vanA; 52% (43/83) possessed the esp gene and 12% (10/83) possessed the hyl gene. Genotyping by SmaI macrorestriction analysis (PFGE) of isolates revealed clonal relatedness between bloodstream isolates and environmental isolates. VRE BSI isolates from two other tertiary care hospitals in the Dublin region showed relatedness by PFGE analysis. MLST revealed four STs (ST17, ST18, ST78 and ST203), all belonging to the clonal complex of hospital-associated strains. CONCLUSIONS: Irish VRE BSI isolates have virulence factor profiles as previously reported from Europe. Typing analysis shows the spread of individual clones within the hospital and between regional tertiary care hospitals. Apart from transmission of VRE within the hospital and transfer of colonized patients between Irish hospitals, no other explanation for the persistently high VREfm BSI rate in Ireland has been found.

Differences in expression of uroplakin III, cytokeratin 7, and cyclooxygenase-2 in canine proliferative urothelial lesions of the urinary bladder.

The expression of immunohistochemical markers that have been used in diagnosis and/or prognostication of urothelial tumors in humans (uroplakin III [UPIII], cytokeratin 7 [CK7], cyclooxygenase-2 [COX-2], and activated caspase 3) was evaluated in a series of 99 canine proliferative urothelial lesions of the urinary bladder and compared to the lesion classification and grade as defined by the World Health Organization / International Society of Urologic Pathology consensus system. There were significant associations between tumor classification and overall UPIII pattern (P = 1.49 × 10(-18)), loss of UPIII (P = 1.27 × 10(-4)), overall CK7 pattern (P = 4.34 × 10(-18)), and COX-2 pattern (P = 8.12 × 10(-25)). In addition, there were significant associations between depth of neoplastic cell infiltration into the urinary bladder wall and overall UPIII pattern (P = 1.54 × 10(-14)), loss of UPIII (P = 2.07 × 10(-4)), overall CK7 pattern (P = 1.17 × 10(-13)), loss of CK7 expression (P = .0485), and COX-2 pattern (P = 8.23 × 10(-21)). There were no significant associations between tumor classification or infiltration and caspase 3 expression pattern.

The Role of Serine Proteases and Antiproteases in the Cystic Fibrosis Lung.

Cystic fibrosis (CF) lung disease is an inherited condition with an incidence rate of approximately 1 in 2500 new born babies. CF is characterized as chronic infection of the lung which leads to inflammation of the airway. Sputum from CF patients contains elevated levels of neutrophils and subsequently elevated levels of neutrophil serine proteases. In a healthy individual these proteases aid in the phagocytic process by degrading microbial peptides and are kept in homeostatic balance by cognate antiproteases. Due to the heavy neutrophil burden associated with CF the high concentration of neutrophil derived proteases overwhelms cognate antiproteases. The general effects of this protease/antiprotease imbalance are impaired mucus clearance, increased and self-perpetuating inflammation, and impaired immune responses and tissue. To restore this balance antiproteases have been suggested as potential therapeutics or therapeutic targets. As such a number of both endogenous and synthetic antiproteases have been trialed with mixed success as therapeutics for CF lung disease.

Pulmonary non-tuberculous mycobacteria in a general respiratory population.

The prevalence of non-tuberculous mycobacterium (NTM) appears to be increasing. Much of the experience in the literature about this emerging organism comes from specialised units or populations such as cystic fibrosis patients. We, therefore, aim to evaluate the experience in a general respiratory population of dealing with patients with positive culture of NTM. We did a retrospective review of medical notes of general respiratory patients from whom NTM were isolated from January 2007 to July 2012. Cystic fibrosis patients were excluded. We reviewed 37 patients' (19 males, 18 females) medical records. A total of 73 positive cultures were reviewed. 28 isolates were from sputum samples alone, 34 isolates were from bronchoalveolar lavage alone and 11 isolates were from a combination of sputum and bronchoalveor lavage (11 isolates), We found that Mycobacterium avium was the most frequently isolated Mycobacterium in our laboratory with 22 (60%) patients had Mycobacterium avium in their pulmonary cultures. Interestingly, Mycobacterium gordonae and mycobacterium intracellulare were the second commonest mycobacterium (4, 11%) cultured. We noted 2 (5%), cases of Mycobacterium szulgai, 2 (5%) cases of Mycobacterium chelonae and 2 (5%) cases of Mycobacterium abscessus. There was 1(3%) case of Mycobacterium malmoense. There is prevalence of NTM in male COPD patients (7, 89%) and femal bronchiectasis (10, 77%) patients. Of our 8 COPD patients, 6 (75%) were on inhaled corticosteroids while 2 (25%) were not. 9 (24%) patients were smokers, 11 (30%) were ex-smokers, 14 (38%) were non-smokers and the smoking status of the remaining 3 (8%) was unknown. Of the 37 patients, only 6 (16%) received treatment. However, 2 patients stopped their treatment due to treatment toxicity. We concluded that the isolation of NTM is not uncommon. Defining NTM disease is difficult and deciding which patient to be treated needs careful evaluation as treatment can potentially be very toxic.

When the answer is a maybe: a retrospective review of indeterminate SARS-CoV-2 results and their associations.

Testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using reverse transcriptase polymerase chain reaction (RT-PCR) may generate indeterminate results (with a cycle threshold ≥30), requiring further investigation to determine the clinical significance. Patient variables which could predict a definitive result ('Detected'/'Not detected') post indeterminate result would aid in optimization of bed management and utilization of limited resources. A retrospective observational study of indeterminate SARS-CoV-2 results in an Irish tertiary hospital from March 2020 to March 2022 was performed to determine whether demographics, comorbidities and immunosuppression were associated with a definitive result upon subsequent investigation. Data was obtained from patient and laboratory records. Analysis of association was explored using Fisher's exact test, and predictability was tested using logistic regression. Of 411 patients with an initial indeterminate test, investigation showed that 299 (72.2%) patients had a subsequent definitive result; 29 were Detected and 270 were Not detected. In the Detected group, a prior diagnosis of COVID-19 was associated with a reduced risk of becoming Detected (crude odds ratio (COR) = 0.10, 95% CI 0.03-0.35). In the Not detected group, vaccinated patients were less likely to have a Not detected result on subsequent testing (adjusted odds ratio (AOR) = 0.57, 95% CI 0.34-0.94). Patients with previous COVID-19 infection were less likely to have a Detected result and vaccinated patients were less likely to have a Not detected result upon investigation of an indeterminate result. This study emphasizes the need for a good clinical and medical history in the management of SARS-CoV-2.

Wildlife reservoirs of bovine tuberculosis worldwide: hosts, pathology, surveillance, and control.

Bovine tuberculosis due to Mycobacterium bovis is a zoonotic disease classically carried by cattle and spilling over into humans primarily by the ingestion of milk. However, in recent decades, there have been many endemic geographic localities where M. bovis has been detected infecting wildlife reservoirs, limiting the progress toward eradication of this disease from cattle. These include cervids in North America, badgers in Great Britain, feral pigs in Europe, brushtailed possums in New Zealand, and buffalo in South Africa. An overview of these wildlife hosts will provide insight into how these reservoirs maintain and spread the disease. In addition, the authors summarize the pathology, current ongoing methods for surveillance, and control. In many instances, it has proven to be more difficult to control or eradicate bovine tuberculosis in wild free-ranging species than in domesticated cattle. Furthermore, human influences have often contributed to the introduction and/or maintenance of the disease in wildlife species. Finally, some emerging themes regarding bovine tuberculosis establishment in wildlife hosts, as well as conclusions regarding management practices to assist in bovine tuberculosis control and eradication in wildlife, are offered.

Distribution of eastern equine encephalomyelitis viral protein and nucleic acid within central nervous tissue lesions in white-tailed deer (Odocoileus virginianus).

An outbreak of eastern equine encephalomyelitis (EEE) occurred in Michigan free-ranging white-tailed deer (Odocoileus virginianus) during late summer and fall of 2005. Brain tissue from 7 deer with EEE, as confirmed by reverse transcriptase polymerase chain reaction, was studied. Detailed microscopic examination, indirect immunohistochemistry (IHC), and in situ hybridization (ISH) were used to characterize the lesions and distribution of the EEE virus within the brain. The main lesion in all 7 deer was a polioencephalomyelitis with leptomeningitis, which was more prominent within the cerebral cortex, thalamus, hypothalamus, and brainstem. In 3 deer, multifocal microhemorrhages surrounded smaller vessels with or without perivascular cuffing, although vasculitis was not observed. Neuronal necrosis, associated with perineuronal satellitosis and neutrophilic neuronophagia, was most prominent in the thalamus and the brainstem. Positive IHC labeling was mainly observed in the perikaryon, axons, and dendrites of necrotic and intact neurons and, to a much lesser degree, in glial cells, a few neutrophils in the thalamus and the brainstem, and occasionally the cerebral cortex of the 7 deer. There was minimal IHC-based labeling in the cerebellum and hippocampus. ISH labeling was exclusively observed in the cytoplasm of neurons, with a distribution similar to IHC-positive neurons. Neurons positive by IHC and ISH were most prominent in the thalamus and brainstem. The neuropathology of EEE in deer is compared with other species. Based on our findings, EEE has to be considered a differential diagnosis for neurologic disease and meningoencephalitis in white-tailed deer.

Identification of a Novel Small Molecule That Enhances the Release of Extracellular Vesicles with Immunostimulatory Potency via Induction of Calcium Influx.

Extracellular vesicles (EVs) transfer antigens and immunomodulatory molecules in immunologic synapses as a part of intracellular communication, and EVs equipped with immunostimulatory functions have been utilized for vaccine formulation. Hence, we sought small-molecule compounds that increase immunostimulatory EVs released by antigen-presenting dendritic cells (DCs) for enhancement of vaccine immunogenicity. We previously performed high-throughput screening on a 28K compound library using three THP-1 reporter cell lines with CD63 Turbo-Luciferase, NF-κB, and interferon-sensitive response element (ISRE) reporter constructs, respectively. Because intracellular Ca2+ elevation enhances EV release, we screened 80 hit compounds and identified compound 634 as a Ca2+ influx inducer. 634 enhanced EV release in murine bone marrow-derived dendritic cells (mBMDCs) and increased costimulatory molecule expression on the surface of EVs and the parent cells. EVs isolated from 634-treated mBMDCs induced T cell proliferation in the presence of antigenic peptides. To assess the roles of intracellular Ca2+ elevation in immunostimulatory EV release, we performed structure-activity relationship (SAR) studies of 634. The analogues that retained the ability to induce Ca2+ influx induced more EVs with immunostimulatory properties from mBMDCs than did those that lacked the ability to induce Ca2+ influx. The levels of Ca2+ induction of synthesized analogues correlated with the numbers of EVs released and costimulatory molecule expression on the parent cells. Collectively, our study presents that a small molecule, 634, enhances the release of EVs with immunostimulatory potency via induction of Ca2+ influx. This agent is a novel tool for EV-based immune studies and vaccine development.

Development of an Evidence biochip array kit for the multiplex screening of more than 20 anthelmintic drugs.

Anthelmintic drugs are used in clinical and veterinary practice for the treatment of infections caused by parasitic worms. Their extensive use in food-producing animals can cause the presence of residues in food. For consumer protection it is necessary to monitor the levels of anthelmintic residues to ensure that they remain within the legally permitted maximum acceptable concentrations. For this purpose, the use of multiplex screening methods is advantageous. Biochip array technology allows the simultaneous determination of multiple analytes from a single sample at a single point in time. This study reports the development of an Evidence biochip array for the multiplex screening of anthelmintic drugs. Simultaneous competitive chemiluminescent immunoassays are employed. The solid support and vessel is the biochip, which contains an array of discrete test sites. The assays were applied to the semiautomated bench-top analyser Evidence Investigator. The aminobenzimidazoles assay detected aminomebendazole, albendazole 2-aminosulphone and aminoflubendazole, the avermectins assay detected emamectin benzoate, eprinomectin, abamectin, ivermectin and doramectin, the benzimidazoles assay detected albendazole sulphone, albendazole, albendazole sulphoxide, oxibendazole, oxfendazole and flubendazole, the thiabendazole assay detected cambendazole, thiabendazole and 5-hydroxythiabendazole and the triclabendazole assay detected ketotriclabendazole, triclabendazole and triclabendazole sulphoxide. The limits of detection ranged from 0.3 ppb (aminobenzimidazoles) to 2.0 ppb (levamisole) in milk and from 0.15 ppb (aminobenzimidazoles) to 6.5 ppb (levamisole) in tissue. The average recovery range was 71-135 %. This multianalytical approach on a biochip platform is applicable to the screening of more than 20 anthelmintic drugs in different food matrices, leading to consolidation of tests and enhancement of the test result output.

Diagnostic accuracy of heart-type fatty acid-binding protein for the early diagnosis of acute myocardial infarction.

OBJECTIVE: The aim of this study was to evaluate the diagnostic efficacy of multiple tests-heart-type fatty acid-binding protein (H-FABP), cardiac troponin I (cTnI), creatine kinase-MB, and myoglobin-for the early detection of acute myocardial infarction among patients who present to the emergency department with chest pain. METHODS: A total of 1128 patients provided a total of 2924 venous blood samples. Patients with chest pain were nonselected and treated according to hospital guidelines. Additional cardiac biomarkers were assayed simultaneously at serial time points using the Cardiac Array (Randox Laboratories Ltd, Crumlin, United Kingdom). RESULTS: Heart-type fatty acid-binding protein had the greatest sensitivity at 0 to 3 hours (64.3%) and 3 to 6 hours (85.3%) after chest pain onset. The combination of cTnI measurement with H-FABP increased sensitivity to 71.4% at 3 to 6 hours and 88.2% at 3 to 6 hours. Receiver operating characteristic curves demonstrated that H-FABP had the greatest diagnostic ability with area under the curve at 0 to 3 hours of 0.841 and 3 to 6 hours of 0.894. The specificity was also high for the combination of H-FABP with cTnI at these time points. Heart-type fatty acid-binding protein had the highest negative predictive values of all the individual markers: 0 to 3 hours (93%) and 3 to 6 hours (97%). Again, the combined measurement of cTnI with H-FABP increased the negative predictive values to 94% at 0 to 3 hours, 98% at 3 to 6 hours, and 99% at 6 to 12 hours. CONCLUSION: Testing both H-FABP and cTnI using the Cardiac Array proved to be both a reliable diagnostic tool for the early diagnosis of myocardial infarction/acute coronary syndrome and also a valuable rule-out test for patients presenting at 3 to 6 hours after chest pain onset.

Toward biophysical markers of depression vulnerability.

A major difficulty with treating psychiatric disorders is their heterogeneity: different neural causes can lead to the same phenotype. To address this, we propose describing the underlying pathophysiology in terms of interpretable, biophysical parameters of a neural model derived from the electroencephalogram. We analyzed data from a small patient cohort of patients with depression and controls. Using DCM, we constructed biophysical models that describe neural dynamics in a cortical network activated during a task that is used to assess depression state. We show that biophysical model parameters are biomarkers, that is, variables that allow subtyping of depression at a biological level. They yield a low dimensional, interpretable feature space that allowed description of differences between individual patients with depressive symptoms. They could capture internal heterogeneity/variance of depression state and achieve significantly better classification than commonly used EEG features. Our work is a proof of concept that a combination of biophysical models and machine learning may outperform earlier approaches based on classical statistics and raw brain data.

The burden of methicillin-resistant Staphylococcus aureus in the delivery of eye care.

BACKGROUND: To describe the clinical presentation, burden and antimicrobial resistance of Methicillin-Resistant Staphylococcus aureus (MRSA) eye infections and to recommend a streamlined protocol for the management of ocular MRSA colonisation detected by pre-operative screening. METHODS: A retrospective review of all ocular samples which resulted in the isolation of MRSA between 1st of January 2013 and 31st of December 2019 at the Royal Victoria Eye and Ear Hospital. RESULTS: A total of 185 samples taken from the ocular surface were MRSA positive. The majority were MRSA colonisation of the ocular surface obtained as part of an MRSA screen (139/6955 patients screened; 2%). Forty-six represented MRSA infections (46/7904 eye samples; 0.58%), most occurring in older patients the majority of whom had known local or systemic risk factors for colonisation. The most common presentation was conjunctivitis (n = 24), followed by pre-septal cellulitis (n = 9). MRSA infections with the poorest clinical outcomes and the longest inpatient stay, were keratitis (n = 6) and post-operative endophthalmitis (n = 2). Our study demonstrated over 60% resistance to azithromycin, fusidic acid and ciprofloxacin, although resistance to chloramphenicol was uncommon. CONCLUSION: This study demonstrates that MRSA infections of the eye most commonly manifest as a mild infection, typically conjunctivitis, and are generally non-sight threatening. The majority of presentations occur in the context of known MRSA risk factors and in an older populous. Resistance to chloramphenicol is rare, thus it remains an excellent first line treatment. Its use to eradicate MRSA from the ocular surface is proposed to streamline the delivery of surgical eye care.